Recent synthetic strategies of spiro-azetidin-2-one, -pyrrolidine, -indol(one) and -pyran derivatives-a review

Spiro-heterocycles have received special attention in medicinal chemistry because of their promising biological activity. Over the years, many synthetic methodologies have been established for the construction of spirocyclic compounds. Spiro heterocycles such as spiro-azetidin-2-one, -pyrrolidine, -indol(one) and -pyran derivatives have been found to exhibit diversified biological and pharmacological activity in addition to their therapeutic properties. In view of these facts, we decided in this review to present representative synthetic approaches of the aforementioned spiro heterocycles, especially in the past 20 years.


Introduction
5][6][7] Spiro compounds are considered spiro heterocyclic if the spiro atom or any atom in either ring are not carbon atoms.Spiro heteroatoms such as nitrogen, oxygen, or sulfur connecting the rings have been commonly observed.Moreover, there are also many classes where one or more heteroatoms appear in one or more of the rings that are joined at a carbon spiro atom.In this review, we focus on four classes of important spiro heterocycles identied as spiroazetidin-2-one, -pyrrolidine, -indol(one) and -pyran derivatives.

Spiro-azetidine-2-one derivatives
Azetidine can be considered as a fairly typical cyclic amine.Strain in the four-membered ring is less than that in the three-membered aziridine system; as a result azetidines show few of the exceptional properties associated with aziridines.In spirocyclic b-lactams, the spiro carbon may be at positions C3 and/or C4 (Fig. 1).
The azetidin-2-one ring has given life-saving penicillin and cephalosporin antibiotics. 8Further exploitation of the b-lactam ring has yielded biologically active new chemical entities exhibiting a variety of activities. 8Over the years, b-lactams have also emerged as versatile building blocks (b-lactam synthon method) for the synthesis of amino acids, alkaloids and toxoids with potential biological properties.Interestingly, spiro[azetidine-2,3 ′ -indole]-2 ′ ,4(1 ′ H)-dione derivatives Ia-e (Fig. 2) showed antibacterial and antifungal activities. 9The antibacterial activity of all the compounds against Staphylococcus aureus as Gram-positive, Escherichia coli and Pseudomonas aeruginosa as Gram-negative bacteria showed good potencies which are comparable to control drugs amoxicillin, gentamycin, and streptomycin.With bromo substituents at the 5 ′ and 7 ′ positions of indoline, Ia-e showed very good activity with MIC values of 6.25-12.5 mg mL −1 .Other derivatives have exhibited moderate activity against all three bacterial strains.Similar structure II (Fig. 2) have shown anthelmintic potency and were evaluated versus standard albendazole.Antibacterial activity was also tested for the synthesized compounds with standard ampicillin against the ve different pathogens Bacillus subtilis, Pseudomonas, aeruginosa, Escherichia coli, Proteus mirabilis and Staphylococcus aureus. 10Spiro-b-lactams III and dispiro-b-lactams IV (Fig. 2) have exhibited good to excellent antimalarial activities against chloroquine-resistant Plasmodium falciparum Fig. 1 Different structures of spiroazetidin-2-ones.

Spiro-pyrrolidine derivatives
Pyrrolidine fragments are widespread in nature; in particular, they are structural units of numerous biologically active compounds 20,21 and natural alkaloid acting as an efficient glucosidase I inhibitors used in the therapy of type II diabetes.Such as azaspirene, 22 and casuarina 23 (Fig. 4).5][26][27] In addition, spiro pyrrolidine-2-ones such as Azaspirene (XI) are found in Nature. 28The marine alkaloid amathaspiramide XII (Fig. 4), isolated from Zealand collection of the marine bryozoan Amathia wilsoni, shows potential antiviral, antimicrobial and cytotoxic activities. 29

Spiro-indol(one) derivatives
In spiroindol(one)s, an indolone ring is substituted with another ring in a spiro arrangement.Spiro indol(one) derivatives occupy a unique place within organic chemical compounds due to their rigidity and 3D-geometrical structure. 30These structural characteristics give rise to the versatile biological properties shown by analogs wherein C-2 or C-3 of the indolyl ring is spiro-cyclized with many heterocycles (XIII-XVII; Fig. 5). 31pirotryprostatin A (XVIII) and spirotryprostatin B (XVIV) showed microtubule assembly inhibition, whereas pteropodine (XX) and isopteropodine (XXI) damped the operation of muscarinic serotonin receptors (Fig. 6). 32,33g. 2 Biologically active spiro azetidin-2-one derivatives I-VI.

Spiro-pyran derivatives
Spiropyrans were discovered in the early twentieth century. 34In the 1920s, Fisher and Hirshbergin observed their photochromic characteristics and reversible reaction. 34Studies on photochromic compounds that have continued up to the present. 35,36piropyran and spirooxazine compounds can undergo reversible structural transformations under the inuence of external stimuli; this induces a color change, as well as changes in their physical and chemical properties. 37,38Spiropyrans and spirooxazines are the most investigated photochromic spiro compounds. 39,40][43] Aly et al. 44 designed and synthesized three series of 2 ′ -aminospiro[pyrano [3,2-c]quinoline]-3 ′ -carbonitrile derivatives XXIIa-f (Fig. 7), hypothesizing that small molecules with a spiro scaffold appended to a pyrano[3,2-c]quinoline analog could act as ATP-noncompetitive Src kinase inhibitors.XXIIb, XXIIc, and XXIId inhibited Src kinase activity with IC 50 's of 4.9, 5.9, and 0.9 mM, respectively.At the same time, they did not affect the MDM2/p53 interaction in HEK293 cells that have been reported to be affected by some spirocyclic compounds.Kinetic analysis for the inhibition of Srctide phosphorylation by XXIId revealed a mechanism of ATP-non-competitive inhibition. 1 mM of XXIId was enough to diminish Src, Fak, and paxillin phosphorylation in the MCF7 breast cancer cell line. 44his work is divided into four distinct classes of spiro heterocycles: spiro-azetidin-2-one, -pyrrolidine, -indol(one) or -pyran derivatives.We deal with building the aforementioned spiro heterocycles, according to the method's scope, selectivity, and reaction mechanism.Previously, a few reviews dealt with the syntheses of these types of spiro heterocycles; 45-47 however, each review article dealt with only one of the four classes mentioned.We concentrate on the synthesis of these spiro compounds in the past 20 years, and discuss the biological activity of some of these classes.

Synthesis of spiro-azetidin-2-one derivatives
With the discovery and structural elucidation of the antibiotic penicillin, the Staudinger synthesis became of major importance in medicinal chemistry, as it allowed the synthesis of penicillin derivatives in the laboratory.Although several alternative methods have been developed, the Staudinger reaction remains the most common method for the synthesis of b-lactams, including spiro-b-lactams. 48Heiran and co-workers synthesized C3 spiro-b-lactams 3 bearing a morpholine ring, in moderate to good yields (41-71%) (Scheme 1) 49 via cyclocondensation of xanthene-9-carboxylic acid (1) and aromatic imines in the presence of tosyl chloride (TsCl) and triethylamine (Et 3 N) in dichloromethane (CH 2 Cl 2 ).
Concerning the reaction mechanism, the rhodium carbenoid 8 obtained from the Meldrum's acid derived diazocompound 6, adds to the azirines 4 or isoxazoles 5 forming adducts 9 or 12, respectively (Scheme 3).Both pathways lead to the same 2-azabuta-1,3-diene 13 product.A parallel Meldrum's acid carbenoid Wolff rearrangement leads to the in situ generation of a ketene 11, which undergoes a [2 + 2] Staudinger cycloaddition with 13 to give b-lactam 7. By using different substituent groups on both azirine and isoxazole, nine different dispirocyclic N-vinyl b-lactams 7 were obtained in low to moderate yields (22-67%). 50 convenient procedure reported by Zhao, Deng and coworkers led to the synthesis of twenty-two enantio-enriched spirooxindole-b-lactams 17 bearing two vicinal stereogenic centers. 51The molecules were obtained in high yields (up to 98%), with good to high diastereo-selectivity and excellent enantioselectivities (Scheme 4).The reaction happens through a homo benzotetramisole (HBTM)-catalyzed Mannich/ lactamization cascade reaction of isatin-derived imines 14 with aryl acetic acids 15 (Scheme 4). 51oncerning the proposed reaction mechanism, 51 the rst step of the reaction involves a reaction between the aryl acetic acid Kirillov et al. synthesized a library of eleven bis(spiro-b-lactams) 24, using the Reformatsky reaction between methyl-1-bromo-cyclohexanecarboxylate (23) and N,N-bis-(arylmethylidene)benzidines 22 as the rst step (Scheme 6). 52inc metal would presumably react with methyl 1-bromocyclohexanecarboxylate to form Reformatsky reagent 25, which would react with the bis-imine to form the corresponding adduct 26 (Scheme 7).The adduct spontaneously cyclizes and forms the lactam ring, affording the bis-spiro-cyclohexane-b-lactam 24 52 Scheme 5 A plausible mechanism for the formation of 17a.
Siemeling et al., 53 reported a metal-free synthesis of racemic spiro-b-lactam derivatives 36 by exploring the reactivity of acyclic diaminocarbenes 33, containing cycloalkyl substituents and using carbon monoxide as building block (Scheme 8).Compounds 33 were synthesized from secondary amines (cyclo-C n H 2n−1 ) 2 NH (n = 5, 6, 7).The amines 27 were formylated with formic acid into compounds 28, which reacted with oxalyl (29) to give the corresponding Vilsmeier complex 30.The latter reacted with the secondary amines to afford formamidinium chlorides 31. 53Anion exchange was performed with ammonium hexauorophosphate to afford the corresponding formamidinium hexauorophosphates 32, which were converted into carbenes 33 upon treatment with NaN(SiMe 3 ) 2 .The synthesis of the spirocyclic b-lactams 36 proceeded via carbonylation of the acyclic diaminocarbenes 33 leading to diaminoketenes 34, which underwent a retro-Wolff rearrangement to give (amido)(amino)carbenes 35 followed by an intramolecular C-H insertion to afford the nal products 36 in yields ranging from 65% to 91% (Scheme 8). 53he synthesis of steroidal spiro-b-lactams 38, bearing a cyanohydrin functional group, from steroidal dienamides 37 has been reported (Scheme 9). 54The spirocyclic products were obtained in low to moderate yields (22-68%) under mild conditions and short reaction time in a one-pot procedure. 54he proposed mechanism involves an intramolecular lactamization of steroidal dienamides 37 via a selective 4-endo N-cyclization, followed by a base-mediated aerobic oxidation which introduces a hydroxyl group at the a-position of the 2azetidinone ring, generating the nal spirocyclic product 38 54 (Scheme 10).
Recently, Nishikawa et al. 55 disclosed the synthesis of a spiroindolenine-b-lactam 42 analogue of alkaloid Chartelline C (Scheme 11).The two-step synthesis comprised the initial formation of a bromoindolenine intermediate 41 via a N-bromosuccinimide (NBS)-mediated chemoselective bromination of bromoenamide 40 at C3, followed by intramolecular lactamization in the presence of 18-crown-6 and K 2 CO 3 /CH 3 CN.The target spirocyclic indolenine-b-lactam 42 was obtained in 92% yield. 55he use of C-aryl-N-substituted nitrones 44 as dipoles in 1,3dipolar cycloadditions with 6-alkylidene-penicillanates 43 to synthesize spiro-b-lactams was explored by Pinho e Melo et al. (Scheme 12). 56The generation of three consecutive stereogenic centers proved to be regio-and stereoselective and afforded chiral spiroisoxazolidine-penicillanates 45 in moderate to good overall yields, using mild conditions. 56The major products 45a were obtained through an endo 1,3-dipolar cycloaddition with addition of the nitrone to the a-side of the b-lactam and were obtained efficiently (26-80% yield); the stereoisomeric exocycloadducts 45b were isolated as minor products (7-27% yield).Two cases were stereospecic, only affording the major product 45a.
Recently Luo et al. reported a phosphine-mediated reductive cyclopropanation reaction of a-keto esters 46 with a-methyleneb-lactams 47 (Scheme 13). 57That metal-free protocol provided the efficient syn synthesis of highly functionalized spirocyclopropyl b-lactams 48 through a mechanism involving the initial oxophilic addition of the phosphine to a-ketoester to generate Kukhtin-Ramirez intermediates (e.g.oxyphosphonium enolate 49b), which can behave as a carbene surrogate.Subsequent Michael addition of these intermediates to the electron decient b-lactam exocyclic double bond followed by a 3-exo-tet cyclization furnishes spirocyclic lactams as diastereoisomeric mixtures. 57he synthesis of a library of spiropyrrolo-quinoline b-lactams 54 was described, using four-component Ugi-adducts 53 as precursors (Scheme 14). 58These spirocyclic-bis-b-lactams 54 were obtained as racemic mixtures in moderate to high yields (54-88%).The Ugi-adducts 53 were synthesized through a fourcomponent reaction of 2-chloro-3-formylquinolines 50, 2chloroacetic acid (15), amines 51, and isocyanides 52 (Scheme 14).The proposed spirocyclization mechanism depends on two sequential cyclizations of the Ugi-adduct, under basic conditions.The rst cyclization involves the g-lactam ring formation via intramolecular aromatic nucleophilic substitution, followed by formation of the b-lactam ring through a nucleophilic acyl substitution. 58

Synthesis of spiroindol(one) derivatives
Spiroindol(ones), which contain a spirocycle fused at the C2 or C3 of the oxindole moiety, are a known subset of indoles and form the core building blocks of highly functionalized organic structures.The procedures to obtain various spiro indolines and spiro indoles reported in the literature 68 can be sorted into categories based on the type and size of the spirocycle that is fused to indole or oxindole such as 3-, 4-, 5-, or 6-membered rings, including different heteroatoms as illustrated in Fig. 8. 68 The electron-rich property of indoles leads to easy oxidation using many reagents.Since catalysis methods in the presence of secure oxidants (H 2 O 2 , Oxone, O 2 ) is highly favorable, Tong and co-workers 69 have introduced three unique, efficient halide catalyzed oxidation processes of tetrahydro-b-carbolines (THCs) indoles applying oxone as the terminal oxidant, which leads to the formation of oxindoles 86, 88 and 90 (Scheme 21). 69pirooxindolopyrrolidine hybrid heterocycles 92, containing b-lactam subunits, were prepared as single diastereoisomers via 1,3-dipolar cycloaddition of Baylis-Hillman adducts 91 with azomethine ylides derived from isatins 71 and a-amino acid 66 under heating at 100 °C in [bmim]Br (Scheme 22). 70The in vitro antimycobacterium tubercular activity of hybrids 92 was assessed against Mycobacterium tuberculosis H37Rv.Members of the series with no substitution or chloro-substitution on the oxindole ring showed the most potent activity with a MIC 0.78 It was tentatively proposed that the reaction involves cleavage of the C-H bond with Rh(III), followed by carbene migratory insertion with the diazo-substrate to obtain an alkyl rhodium intermediate 105.Then, a formal Lossen rearrangement offers isocyanate 106, which, via further nucleophilic addition at the isocyanate, intramolecularly generates the nal compound 101 (Scheme 25). 72roviding an electron-withdrawing moiety for alkylidenyloxindoles acting as dipolarophiles, the asymmetric Michael addition/cyclization cascade reaction of 3-isothiocyanato oxindoles 107 and 3-methyl-4-nitro-5-isatylidenyl isoxazoles 108, catalyzed by quinine, yielded enantiomerically enriched isoxazole-dispirobisoxindoles 109 (Scheme 26). 73Although enantioselectivities were found to be dependent on the protecting group of the nitrogen atom of the isothiocyanato oxindole 107 and the isatylidenyl isoxazole 108, and on the electronic character of the substitution of both aromatic rings, excellent diastereo-selectivity was achieved in almost all cases and high reactivity was observed, with reaction times of only 30 min. 73he synthesis of complex spiro heterocyclic compounds 113 has been pursued, by cycloaddition of in situ generated azomethine ylides with 3-alkylidene-2-oxindoles 110 as dipolarophiles.This acetic acid-promoted three component reaction 110, aldehydes 111 and pyrrolidine (112) gives the resulting cycloadducts with good yields and diastereoselectivity (50-80% presence of trimethylamine (Et 3 N) accomplished the regioselective formation of spiro pyrrolidine oxindoles 115/116 (Scheme 28).The main products 115 were formed in most cases as a white precipitate in the reaction mixture, and could be separated by simple ltration to give the single diastereoisomer 115 (in up to 75% yield).The minor isomer 116 could be isolated from the mother liquor using preparative HPLC. 75ripathi et al. 76 have described the regioselective synthesis of hexahydrospiro[indoline-3,3 ′ -pyrrolizine]-2-ones 120 in good-toexcellent efficiencies through [3 + 2] cycloaddition.The products were obtained via reaction of substituted 3-pyran-2-ones 118, isatin derivatives 71, and L-proline (119) at ambient temperature (Scheme 29).The chalcones 118 used in this reaction were produced via aldol condensation of substituted benzaldehydes 111 and 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2one (117) in dry chloroform (CHCl 3 ) using a catalytic amount of piperidine (Scheme 29). 76cheme 30 shows that the dispiro-2 ′ ,4 ′ -(2-oxindolo)indolizidine 122 skeleton 77 was obtained at room temperature in EtOH or water (83-97% yield).Condensation between tetrahydroisoquinoline 70 and isatin derivatives 71 provided an azomethine ylide intermediate, whose subsequent cycloaddition with the appropriate dipolarophile gave the target molecules 122 as single diastereoisomers.Curiously, these reactions occurred in the absence of a basic agent.Inexpensive ZnO nanoparticles (NPs) were tested in order to determine their recyclability.Unfortunately, the efficiency of the nano-catalyst declined at every cycle, and aer the third one the nanoparticles resulted as aggregates 77 (Scheme 30).Synthesis of N-allyl-bis(methoxyphenylmethylidene) piperidone (127), starting with piperidin-4-one$HCl (123), is outlined in Scheme 31.The spirooxindole-pyrrolidine 128 was extracted in good yield (86%) via the cycloaddition of dipolarophile 127 78 with the azomethine ylide generated in situ from isatin derivatives 71 and sarcosine (56) at reux in CH 3 OH for 1 h.The same reaction was performed in [bmim]Br at 100 °C (Scheme 31).TLC analysis of the reaction mixture revealed completion of the reaction in about 30 min with formation of the sole reaction product.The reaction mixture was then extracted with ethyl acetate and further puried by column chromatography.The reaction in [bmim]Br afforded a slightly better yield (90%) of 128 over the conventional heating employing CH 3 OH (86%) (Scheme 31). 78an's group 79  Review RSC Advances fused with both oxindole and pyrazolone (131) with four adjacent stereocenters and two adjacent spiro-quaternary chiral centers, in high efficiencies and stereoselectivities (Scheme 32). 79 mild catalyst-free [3 + 2] cyclization of dihydroisoquinolines 132 and the isatin-based Morita-Baylis-Hillman (MBH) carbonates 133 has been investigated (Scheme 33). 80The combination of dihydroisoquinolines and the spirooxindole skeletons was achieved, leading to richly decorated spiro heterocycles 134 in moderate to good yields with good stereocontrol. 80he one-pot three-component cycloaddition reaction of 2arylmethylidene-5,6-dimethoxyindenones 135 with azomethine ylides generated in situ from 5-(triuoromethoxy)isatin (71) and tryptophan/phenylalanine 66 in [bmim]Br furnished the spiropyrrolidine heterocyclic hybrids 136 in moderate to good yields.Among the spiro pyrrolidine heterocyclic hybrids, the indole based uorinated compound with a methoxy substituent at the meta-position of the aryl ring exhibited the utmost potent AChE and BChE inhibition with IC 50 values of 1.97 ± 0.19 mM and 7.08 ± 0.20 mM, respectively (Scheme 34). 81he three-component domino reaction of isatin derivatives 71, 1,3-diketone (138), and hydantoin (137) without catalyst did not succeed either in the absence of solvent, or in water or EtOH as solvents: the desired product 139 was not obtained aer stirring for 12 h (no result). 82However, using either piperidine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU), or taurine (2-aminoethanesulfonic acid) as a catalyst in H 2 O as solvent, the desired products 139 were obtained in appreciably good yield (Scheme 35).But when the reaction was carried out in the presence of L-proline as a catalyst using H 2 O as a solvent, comparatively better yield of the desired product was obtained. 82An excellent yield of 139 was obtained when taurine (28 mol%) was used as a catalyst using H 2 O as a solvent (Scheme 35). 82piro[indoline-3,5 ′ -pyrrolo[1,2-c]thiazol]-2-one (142) was synthesized as shown in Scheme 36.One-pot multi-component condensation of a,b-unsaturated dienones 140 with the isatin derivatives 71 and amino acid derivatives 141 (L-4-thiazolidinecarboxylic acid) in CH 3 OH at reux produced the spirooxindole series 142 (Scheme 36). 83The anticancer activities of compounds 142 were tested against colon (HCT-116), prostate (PC-3), and hepatocellular (HepG-2) cancer cell lines; some compounds inhibited colony formation, cell migration, arrested cancer cell growth at G2/M, and induced apoptosis through intrinsic and extrinsic pathways. 83he synthesis of racemic spiro examples of the spiro cycloadducts with 80-90% yield (Scheme 37). 84Other examples were provided similarly. 85,86Biological evaluation of the so-obtained spiro(2-oxindolo)pyrazoline library showed antiproliferative activity in HCT-116p53(+/+) human colorectal cancer cell line with two derivatives displaying good activities (144a: IC 50 = 13.1 ± 1.0 mM, 144b: IC 50 = 10.9 ± 0.8 mM), see Scheme 37.Both spiro(indolo)pyrazolines 144a,b were able to induce apoptosis and cell cycle arrest.Cytotoxic effects induced by 144a occurred in cancer cells without eliciting cells death in non-malignant human colon broblasts.Furthermore, it was demonstrated that the combination of 144a with subtoxic concentrations of the chemotherapeutic agent 5-uorouracil exerted a synergistic inhibitory effect on HCT-116 colon cancer cell proliferation. 84heibani and co-workers 87 reported that cycloaddition between isatin-3-imines 14 and pyridinium or isoquinolinium salts gave racemic spiro(2-oxindolo) imidazolines 146/148 in 90-95% yield.Mild conditions, operational simplicity and easily accessible starting materials were features of these cycloadditions (Scheme 38). 87The cycloaddition reactions involved the nucleophilic attack by the isoquinolinium-ylides on isatin-3-imines 14 which act as a dipolarophile. 87ddition of 3-diazoisatins 99 to O-propargyl salicylaldehydes 149 in the presence of copper(I) thiophenecarboxylate [(Cu(I)TC] in dichloromethane (CH 2 Cl 2 ) as solvent gave the spiro(furo[3,2c]chromene)-2-oxindoles 152 (ref.88) (Scheme 39).Mechanistically, the reaction between 3-copper(I)carbene-diazoisatins and salicylaldehydes involved the generation of the carbonyl ylide intermediates 151, whose subsequent stereoselective intramolecular cycloaddition gave products 152 in 61-84% yield as single diastereoisomers (Scheme 39). 88In the same reaction conditions, a bis-propargylated salicylaldehyde 153 reacted with diazoisatin 99 giving the complex bis-cycloadduct 154 as single diastereoisomer. 88 regio-and diastereo-selective three-component reaction between aldehydes 111, dibromoformaldoxime (83b) and 2oxindole (155) has been pursued in the presence of ferrite-silica nanoparticles decorated with Au(0) nanoparticles (Fe 3 O 4 @SiO 2 @Au) as the nano-catalyst (Scheme 40).From the synthetic standpoint, a sequential Knoevenagel condensationnitrile oxide cycloaddition led to the formation of spiro(2oxindolo) isoxazolines 157 under mild reaction conditions in 78-85% yield.89 Both bromonitrile oxide and 3-alkylidene-2oxindole, were generated in situ, the former by action of sodium hydrogen carbonate (NaHCO 3 ) on dibromoformaldoxime, the latter by Knoevenagel condensation between 2-oxindole and aromatic aldehydes.The spiro(2-oxindolo) isoxazoline cycloadducts apparently result from the regioselective attack of bromonitrile oxide on the carbon-carbon double bond of the 3alkylidene-2-oxindole.From the mechanistic standpoint, Au(0) nanoparticles act as efficient catalysts by activating bromonitrile oxide through the lanthanide contraction effect.90 The synthesis of spirooxindole-d-lactams from oxoindolederived a-aryl-b-amino acids has been described.91 Oxoindole derivatives 159 were obtained stereoselectively by an organocatalyzed asymmetric Mannich reaction between homophthalic anhydrides 158 and isatin-derived N-Boc imines 14 with Scheme 39 Intramolecular cycloaddition of the indolic carbonyl ylide 151.92 The target spirocyclic lactams 165 were obtained in good yields (up to 94%) and good to excellent enantioselectivities (87-97% ee).The reaction exhibited good functional group tolerance although attempts to carry out the reaction with N-Boc-imine or N-Ac-imine derivatives did not lead to the formation of the desired products.92 The synthesis of chiral spiro-d-lactams with antimalarial activity was reported via two different strategies using bicyclic dlactam 166, derived from S-tryptophanol, as building block (Scheme 43).93 Compound 166 reacted with 2,4-dinitro-uorobenzene via aromatic nucleophilic substitution to afford compound 167.Next, reduction with H 2 /Pd-C followed by TiCl 4 / triethylsilyl hydride promoted spiro-cyclization led to spiro oxindole-d-lactams 168 and 169 (Scheme 43).
The three-component approach to the synthesis of spiro indoline d-lactams 172, used 2-bromobenzyl bromides 171 as the third reaction component along with a-isocyano d-lactams 170 and benzylamine (51), in the presence of a Pd/Cu catalytic system (Scheme 44). 94he proposed mechanism for this multicomponent reaction involves initial Pd-catalyzed benzylation of a-isocyano d-lactams 170 to give intermediate 173 which undergoes a copper-Scheme 40 Fe 3 O 4 @SiO 2 @Au-catalyzed three component reactions between 2-oxindole, aromatic aldehydes and dibromoaldoxime.
Scheme 41 TFA-mediated N-Boc deprotection/intramolecular N-acylation reaction of oxoindole-derived a-aryl-b-amino acids.mediated in situ amine addition to the isocyanide moiety and nally isomerization to generate 174. 94In the nal step, the intramolecular N-arylation of palladium complex 175 via Pd/Cu catalysis generates the indoline core, affording spirocyclic d-lactams 172 in moderate to good yields (51-73%) (Scheme 45). 94cently, an efficient catalytic asymmetric three-component reaction of isoquinolines 76, allene dicarboxylates 176 and methylene indolinones 110 was realized for the synthesis of spiroindolino-pyrido[2,1-a]isoquinolines 178. 95In the presence of the chiral N,N ′ -dioxide/Mg(OTf) 2 catalytic system, the reaction proceeded via the nucleophilic addition and proceeded via the simultaneous Si/b-Re face attack, affording the exocyclic alkene intermediate 180.Finally, intramolecular [1,3]-hydrogen shi resulted in the isomerized product 178 (Scheme 47). 95hojasteh-Khosro and Shahbazi-Alavi 96 developed an efficient and rapid procedure for the formation of spiro[benzo [5,6]  chromeno [2,3-c]  98 The proposed reaction mechanism for the synthesis of 193 or 194 is illustrated in Scheme 51. 98  conditions, 196 remains at the step of enol formation, so the masked carbonyl's reactivity is less than that of the ester part.Therefore, intramolecular cyclization happens in the ester group of the coumarin species and produces intermediate 197, and eventually stable compound 194 forms via ring-opening of the coumarin.On the other hand, by using acid, tri-substituted methane intermediate 196 remains as protonated form 199, containing the active protonated carbonyl group (ketone) 200, so ring closure happens intramolecularly by involving the ketone group of the coumarin instead of the ester group, and product 193 was formed (Scheme 51). 98n order to expand the substrate scope, the same authors have prepared another spiro-oxindole fused with coumarindihydropyridine-isooxazole tetracycle 202 by applying 5amino-3-methylisoxazole (201) (Scheme 52). 98ripathi 99 has introduced an efficient multicomponent synthetic method for the formation of spiro[indoline-3,2 ′ -quinazoline]-2,4 ′ (3 ′ H)-diones 204 from isatoic anhydride (203), isatin derivatives 71, and primary amines 51, which was catalyzed by b-cyclodextrin in an aqueous medium (Scheme 53).Due to the use of environmentally friendly catalysts and green solvents, this is a green method to produce valuable spiroheterocycles. 99ly et al.Generally, arylideneindolinones 110 bearing either electrondonating or electron-withdrawing groups at the 5-or 6-position provided good yields.Furthermore, electron-donating groups led to better diastereoselectivity.The synthetic potential of this catalytic system was conrmed by the gram-scale production of the products (Scheme 57).reductive amination with formaldehyde according to an Eschweiler-Clarke protocol, 112 which gave the corresponding dimethylamino derivative 246. 111

Conclusion
This review summarizes various methodologies used to synthesize spiro-azetidine-2-one, spiro-pyrrolidine, spiroindol(one), and spiro-pyran compounds with enormous scope in pharmaceutics.During the past two decades, ample attention has gone into replacing the age-old methods associated with volatile solvents, harsh reaction conditions, and poor yield of products.New methods have been developed to mitigate these shortcomings as well as increase quantitative yields.In this review, new methods have been systematically catalogued for the convenience of readers.In addition, we focused light on some spots dealing with biological activity of the aforementioned spiro heterocycles.

Fig.
Fig. Representative examples of biologically active spiro cyclic b-lactam VII-X.
15 and pivaloyl chloride which generates a mixed anhydride 18, responsible for the HBTM acylation which afforded intermediate 19 (Scheme 5).Deprotonation of intermediate 19 occurs on the C1-ammonium enolate to give intermediate 20, which subsequent Si-face-attack Mannich reaction afforded intermediate 21.On the last step of the catalytic cycle, intermediate 21 underwent an intramolecular lactamization providing the desired cis-spiro-oxindole b-lactam product 17a and regenerating the HBTM catalyst (Scheme 5).
(2-oxindolo)pyrazolines 144 was accomplished by treating hydrazonoyl chlorides 143 with 3alkenyl-2-oxindoles 110 in the presence of triethylamine (Et 3 N) as the organic basic agent and CH 2 Cl 2 as a solvent.The regioselective cycloaddition of the dipolar intermediate gave 19
Scheme 47 Rational pathway for the formation of 178.
Scheme 49 Synthesis of spiro compounds 189 and 191.

Scheme 51 A
Scheme 51 A rational mechanism for the formation of 193 and 194.
Scheme 55 Utility of NMSM for the one-pot synthesis of fused spiro 4H-pyrans 210.